The invention relates generally to novel polynucleotides, particularly those that are differentially expressed in cancer, in particular, pancreas, colon, and breast cancer.
Pancreatic Cancer
Cancer of the pancreas is the fifth leading cause of cancer death in the United States. According to the American Cancer Society, approximately 28,000 people will die of pancreatic cancer in the United States in 1998. The pancreas is a tongue-shaped glandular organ composed of both endocrine and exocrine gland portions, as well as ducts that connect the pancreas to the bile duct and small intestine. The endocrine portion of the pancreas secretes hormones, such as insulin and glucagon, which are involved in blood sugar regulation, into the bloodstream. The exocrine portion of the pancreas produces pancreatic enzymes involved in the digestion of fats and proteins; these enzymes are delivered to the bile duct and into the small intestine.
Tumors of the endocrine pancreas have unique biological characteristics, and therapy is relatively effective. Neoplasms of the exocrine pancreas develop insidiously, and therapy is relatively ineffective. When considered by histological type, ductal cell adenocarcinomas are the most frequent type of exocrine pancreas tumors, accounting for approximately 82% of all tumors of the exocrine pancreas.
Although early and accurate diagnosis can thus be extremely important in treatment success, conventional screening tests for detecting pancreatic cancer in asymptomatic persons are inadequate. Imaging procedures such as magnetic resonance imaging and computed tomography are too costly to use as routine screening tests, while more accurate tests such as endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound are inappropriate for screening asymptomatic patients due to their invasiveness. Abdominal ultrasonography is a noninvasive screening test, but there is little information on the efficacy of abdominal ultrasound as a screening test for pancreatic cancer in asymptomatic persons. In symptomatic patients with suspected disease it has a reported sensitivity of 40-98% and a specificity as high as 90-94%. Conventional ultrasonography is limited by visualization difficulties in the presence of bowel gas or obesity and by its range of resolution (2-3 cm). Even tumors less than 2 cm in diameter are frequently associated with metastatic disease, thus limiting the ability of ultrasound to detect early disease.
Most persons with pancreatic malignancy have elevated levels of certain serologic markers such as CA19-9, peanut agglutinin, pancreatic oncofetal antigen, DU-PAN-2, carcinoembryonic antigen, alpha-fetoprotein, CA-50, SPan-1, and tissue polypeptide antigen (Rhodes et al. (1990) Bailleres Clin. Gastroenterol. 4:833; Steinberg (1990) Am. J. Gastroenterol. 85:350; Satake et al. (1990) Int. J. Pancreatol. 7:25; Satake (1991) Int. J. Pancreatol. 9:93). None of these markers is, however, tumor specific or organ specific (Satake (1991), supra). Elevations of various serologic markers also occur in significant proportions of persons with benign gastrointestinal diseases or malignancies other than pancreatic cancer (Carter (1990) Gut 31:494; Rhodes et al. (1990), supra; Satake et al. (1990), supra; Satake (1991), supra). Most of these markers have been studied exclusively in high-risk populations, such as symptomatic patients with suspected pancreatic cancer. CA19-9 has probably achieved the widest acceptance as a serodiagnostic test for pancreatic carcinoma in symptomatic patients, with an overall sensitivity of approximately 80% (68-93%) and specificity of 90% (73-100%); sensitivity was highest in patients with more advanced disease (Steinberg (1990), supra; Satake et al. (1990), supra). Among healthy subjects, CA19-9 has good specificity (94-99%) (DelVillano et al. (1983) Clin. Chem. 29:549; Ritts et al. (1984) Int. J. Cancer 33:339; Fabris et al. (1988) Am. J. Gastroentrol. 83:549) but nevertheless generates a large proportion of false-positive results due to the very low prevalence of pancreatic cancer in the general population (Frebourg et al. (1988) Cancer 62:2287; Homma et al. (1991) Int. J. Pancreatol. 9:119). The predictive value of a positive test could be improved if a population at substantially higher risk could be identified.
Breast Cancer
Breast cancer is the most common malignant neoplasm in women worldwide. This is also true in the United States, where the annual incidence was 104.6 new cases per 100,000 in 1989. The lifetime risk of breast cancer in the United States is estimated to be about one case for every eight women. Most breast cancers are invasive adenocarcinomas arising from the ductal lobular epithelial unit (Fisher (1975) Cancer 36:1), and the vast majority of patients have infiltrating ductal carcinomas. Overall, breast cancer makes up 32 percent of all cancer in U.S. women. The annual mortality rate from breast cancer has remained at about 27 deaths per 100,000 for many years despite improvements in medical management (Cancer Treatment, 4th Ed. C. Haskell, ed. (1995) W.B. Saunders Co). Current treatments include surgical resection, ionizing radiation therapy, systemic chemotherapy, endocrine therapy, or a combination of the foregoing.
Early diagnosis is of paramount importance in reducing mortality. Currently, screening and diagnostic methods include mammography and self-examination. Certain serum markers may be indicative of metastasis. Serial measurements of serum calcium and alkaline phosphatase are of established value for monitoring patients with known metastatic disease. Carcinoembryonic antigen (CEA) has been used to assess the response of patients to chemotherapy. The role of other potential tumor markers, such as CA549 and CA15-3, is currently under investigation.
Colorectal Cancer
Colorectal cancer is a major health problem in most affluent countries. In the United States, it is the fourth most frequent site for a primary malignant neoplasm, with approximately 149,000 new cases and 56,000 deaths expected in 1994. The vast majority of primary colorectal malignant neoplasms are epithelial adenocarcinomas. Current treatments include surgical resection, and single-agent and combination chemotherapy.
Current screening and diagnostic methods include, for asymptomatic people, tests for occult blood in the stool and screening flexible sigmoidoscopy. For symptomatic patients, diagnostic tests include barium enema, colonoscopy, and ultrasound.
Inadequacies of conventional diagnostic methods for the above-mentioned cancers highlight the need for diagnostic and therapeutic methods and compositions, as well as for a better understanding of the disease to provide the basis for more rationale and more quickly responsive therapy. The present invention addresses this need by providing nucleotide sequence that are differentially expressed in these diseases.
Related Literature
A human mRNA, designated xe2x80x9cKIAA0858xe2x80x9d, was identified in human brain tissue, and is described in Nagase et al. (1998) DNA Res. 5:355-364. The nucleotide sequence of KIAA0858 is provided under GenBank Accession No. AB020665. A human mRNA was identified in pancreas tissue, its predicted translation product encodes a zinc-finger domain-containing protein, and its sequence is provided under GenBank Accession No. U90654.
The present invention is based on the discovery of polynucleotides that represent a gene that is differentially expressed in restricted types of cancer cells, specifically, colon, breast, and pancreatic cancer cells, particularly cancerous colon, breast, and pancreatic ductal epithelial cells. The present invention features a human HX2004-6 polypeptide and nucleotide sequences encoding HX2004-6 polypeptides. In a particular aspect, the polynucleotide is the nucleotide sequence of SEQ ID NO:1 and SEQ ID NO:3. In addition, the invention features polynucleotide sequences that hybridize under stringent conditions to SEQ ID NO:1 or SEQ ID NO:3. In related aspects the invention features expression vectors and host cells comprising polynucleotides that encode a human HX2004-6 polypeptide. The present invention also provides antibodies that bind specifically to a human HX2004-6 polypeptide.
The invention further provides methods using the polynucleotides and antibodies of the invention. The methods include methods for producing human HX2004-6 polypeptides; methods for detecting the presence of an HX2004-6 polypeptide or an HX2004-6 polynucleotide in a biological sample; methods for detecting cells expressing HX2004-6; methods for identification of individuals at risk for pancreatic, colon, or breast cancer by detecting alteration in HX2004-6 coding and regulatory sequences and HX2004-6 expression levels.
Another object of the invention is to provide an isolated human HX2004-6 polypeptide-encoding polynucleotide for use in generation of non-human transgenic animal models for HX2004-6 gene function, particularly xe2x80x9cknock-inxe2x80x9d HX2004-6 non-human transgenic animals characterized by excess or ectopic expression of the HX2004-6 gene.
The invention further provides screening methods to identify agents that modulate expression of human HX2004-, for example, transcription and/or translation of a human HX2004-6 polynucleotide. Of particular interest are those compounds that reduce human HX2004-expression, which compounds can be further evaluated for use in treating adenocarcinomas of breast, colon and pancreatic ductal epithelial cell origin.
These and other objects, advantages and features of the present invention will become apparent to those persons skilled in the art upon reading the details of the invention more fully set forth below.
The invention will now be described in further detail.